Missed postoperative metabolic acidosis associated with sodium-glucose transporter 2 inhibitors in cardiac surgery patients: a retrospective analysis

The increasing use of sodium glucose transporter 2 inhibitors (SGLT2i) for treating cardiovascular (CV) diseases and type 2 diabetes (T2D) is accompanied by a rise in euglycemic diabetic ketoacidosis occurrences in cardiac surgery patients. Patients undergoing cardiac surgery, due to their pre-existing CV disease which often requires SGLT2i prescriptions, face an increased risk of postoperative metabolic acidosis (MA) or ketoacidosis (KA) associated with SGLT2i, compounded by fasting and surgical stress. The primary aim of this study is to quantify the incidence of SGLT2i-related postoperative MA or KA and to identify related risk factors. We analyzed data retrospectively of 823 cardiac surgery patients, including 46 treated with SGLT2i from November 2019 to October 2022. Among 46 final cohorts treated preoperatively with SGLT2i, 29 (63%) developed postoperative metabolic complications. Of these 46 patients, stratified into two categories based on postoperative laboratory findings, risk factor analysis were conducted and compared. Analysis indicated a prescription duration over one week significantly elevated the risk of complications (Unadjusted OR, 11.7; p = 0.032*; Adjusted OR, 31.58; p = 0.014*). A subgroup analysis showed that a cardiopulmonary bypass duration of 60 min or less significantly raises the risk of SGLT2i-related postoperative MA in patients with a sufficient prescription duration. We omitted the term "diabetes" in describing complications related to SGLT2i, as these issues are not exclusive to T2D patients. Awareness of SGLT2i-related postoperative MA or KA can help clinicians distinguish between non-life-threatening conditions and severe causes, thereby preventing unnecessary tests and ensuring best practice.

www.nature.com/scientificreports/patient prescribed an SGLT2i other than Empagliflozin or Dapagliflozin was excluded for study consistency.Subsequently, the refined cohort consisted of 46 patients, stratified into two categories based on postoperative laboratory findings: the MA group (pH < 7.35 and HCO3-≤ 22 mEq/L, n = 27) and the non-MA group (pH ≥ 7.35 or HCO3-> 22 mEq/L, n = 19).[Fig.1] In both groups, we collected data on preoperative baseline characteristics, intraoperative factors, and immediate postoperative factors to identify risk factors associated with SGLT2i-related KA or MA.
To clarify, the postoperative period generally refers to the time starting immediately after surgery, typically beginning with the patient's admission to the ICU.At our institution, preoperative glycemic control in T2D patients is managed with a glucose-insulin mix or glucose-insulin-potassium (GIK) solution, following endocrinologist consultation.Postoperatively, we follow ICU protocol to maintain blood glucose between 110 and 150 mg/dL using insulin infusion 20 .Both preoperative and postoperative insulin infusions are administered as mentioned earlier.

Statistical analysis
The IBM SPSS software, version 21.0, was utilized for data analysis.Continuous variables were expressed as mean ± standard deviation (SD) or as median (25th and 75th percentiles), while categorical variables were presented as frequency counts and percentages (n%).Independent t-tests and χ 2 tests were employed, as appropriate, to compare variables such as types of SGLT2i, arterial blood gas analyses (ABGA), duration of mechanical ventilator (MV) support, and length of ICU stay between the postoperative MA group and the non-MA group.The Mann-Whitney U test was used to compare the number of inotropes administered between the two groups.Univariate logistic regression analysis was conducted to identify potential associated risk factors in preoperative, intraoperative and postoperative period.The covariables for the multivariable logistic regression model were selected based on clinical judgement and a comprehensive review of existing literature.The variables evaluated in this model include Body Mass Index (BMI), the status of preoperative insulin usage, duration of SGLT2i prescription and cessation, operating time, CPB duration, and postoperative insulin utilization.Also, CPB running time was divided into before and after 60 min to indicate a short CPB running time.While there is no basis www.nature.com/scientificreports/for specifically choosing 60 min, but generally, one shot of cardioplegia lasts between 60 to 90 min, depending on the type of cardioplegia used.We set 60 min as the criterion for short CPB time, which is also related to the reduction of plasma protein concentration and the duration or amount of ultrafiltration.The impact CPB duration on postoperative MA or KA associated with SGLT2i was examined in a subgroup analysis of patients with sufficient prescription duration.The odds ratio (OR) or hazard ratio (HR) are presented with a 95% confidence interval(CI) for inferential statistics, and a two-sided P-value of less than 0.05 was statistically significant.

Ethics approval and consent to participate
Given the retrospective design of this study and the fact that there was no harm to participants, the Institutional Review Board of Incheon Sejong Hospital approved a waiver for the requirement of informed consent.(IRB approval no.2022-09-001).All personal and clinical data, including laboratory results and patient outcomes, were obtained from the patients' medical records.All the methods were carried out in accordance with relevant guidelines and regulations.

Demographic and postoperative profile of the study cohort
In a retrospective study of 46 patients undergoing cardiac surgeries, 26 (56.5%) were prescribed dapagliflozin, and 29 (63%) developed postoperative SGLT2i-related MA.Clinical and demographic characteristics of the study population are shown in [Table 1].The average of age was 62.2 ± 11.14 year and BMI was 24.78 ± 3.3 kg/m 2 .Of the 46 patients, 33 (71.3%) were men, and 42 (91.3%)had a past medical history of T2D.Blood glucose levels in both groups were investigated, and no statistical difference was found (117.7 ± 61.2 vs. 191.4± 35.3; p = 0.373).Furthermore, no statistically significant difference was noted between the two groups regarding the duration of MV support or the length of ICU stay.When evaluating the quantity of inotropes administered, instances of postoperative MA associated with SGLT2i exhibited a greater proportion of patients with a high inotropic demand (more than 2 agents); however, this variance was not statistically significant.(5 (17.2%) vs. 0 (0%); p = 0.140).

Clinical variables and incidence of SGLT2i -related postoperative MA
The potential risk factors, preoperative, intraoperative and postoperative variables, associated with SGLT2irelated postoperative MA were examined in univariate and multivariable regression analyses [Table 2].We included factors with a p-value of less than 0.2 in the univariate analysis as significant variables in the multivariable logistic regression test.Additionally, we incorporated the presence of insulin-dependent T2D, a previously known precipitating factor for DKA, and the cessation time of more than 72 h for SGLT2i, as specified in the guidelines for the prevention of EDKA, into the analysis.

Preoperative factors
In the unadjusted analysis, several factors-including age, sex, BMI, premedical history of T2D, hemoglobin A1C (HbA1c) levels, preoperative glucose-insulin mixed infusion, use of other T2D medications, duration of SGLT2i cessation, and baseline estimated glomerular filtration rate (eGFR)-did not exhibit statistically significant differences between the postoperative MA group and the non-MA group.However, a prescription duration of SGLT2i of more than one week was associated with SGLT2i-related postoperative MA (OR, 11.7; 95% CI 1.65-237; p = 0.032*).In the multivariable analysis, this association remained significant (adjusted OR, 31.58;95% CI 1.97-505.23;p = 0.014*).

Intraoperative factors
Regarding intraoperative factors, we assessed the types of operations conducted, the duration of these operations, the utilization of CPB, the duration of CPB running time, instances where CPB exceeded 60 min (referred as CPB 60), and the volume of ultrafiltration.In the univariate analysis, no statistically significant differences in intraoperative factors between the two groups were observed.In the adjusted model, which examined potential risk factors associated with postoperative MA or KA related to SGLT2i-including operation time and CPB 60-no statistical significance was found.

Postoperative factors
In both the univariate and multivariable models, the immediate postoperative administration of insulin infusion did not show any statistically significant differences between the group with postoperative MA related to SGLT2i and the non-MA group.(Unadjusted OR: 0.44; 95% CI 0.12-1.49;p = 0.197; Adjusted OR: 0.40; 95% CI 0.07-2.22;p = 0.298).

Subgroup analysis: impact of CPB running time on SGLT2i-related postoperative MA in patients with sufficient prescription duration
A subgroup analysis was conducted to assess the impact of CPB duration in patients with a sufficient SGLT2i prescription duration over 7 days (N = 40).Table 3 shows that a CPB duration ≤ 60 min is associated with a significantly higher risk of SGLT2i-related postoperative MA (HR 2.94; 95% CI 0.50-5.38,p = 0.018*).

Discussion
For individuals with T2D, the prevalence of DKA or EDKA following the introduction of SGLT2i remains uncertain.In predominantly non-operative settings, in clinical trials involving SGLT2i for T2D treatment, the incidence of DKA ranged from 0.2 to 0.8 cases per 1000 patient-years 21,22  www.nature.com/scientificreports/SGLT2i might not be higher than in the wider diabetic population; however, clinical trials may not fully reflect real-world incidences.In a meta-analysis of 36 trials that evaluated T2D drug therapies, SGLT2i were the only class of drugs associated with an increased risk of DKA compared to other therapies 23 .A large-scale study from Canada and the United Kingdom, involving over 350,000 patients and 500 DKA cases, noted an increased risk with SGLT2i (dapagliflozin, empagliflozin, canagliflozin) compared to dipeptidyl peptidase-4 inhibitors, with respective incidence rates of 2.03 and 0.75 per 1,000 patient-years, and heightened DKA risks associated with dapagliflozin (HR: 1.86) and empagliflozin (HR: 2.52) 24 .www.nature.com/scientificreports/As known, several factors are recognized to precipitate DKA in the context of SGLT2i use.Patient characteristics such as insulin deficiency, commonly seen in latent autoimmune diabetes in adults, type 1 diabetes, or some individuals with long-standing T2D, have been noted 25 .Metabolic stressors like surgical interventions, vigorous exercise, myocardial infarctions, strokes, severe infections, and prolonged fasting have also been identified as significant contributors 25,26 .Other risk variables that could potentially predispose an individual to KA include pancreatic insulin deficiency, reductions in prescribed insulin dosage, caloric restriction, alcohol misuse and acute febrile illness.
Regarding perioperative patients with SGLT2i-related KA or MA, Thiruvenkatarajan et al. reported a prevalence of 89% for postoperative SGLT2i-related EDKA in their systematic review 15 .Blau. et al. using FDA data, found a comparable incidence rate of 71% (29 out of 51) 16 and Murugesan, K.B. observed a 70.8% (17 out of 24) for SGLT2i-associated EDKA in cardiac surgery patients 17 .Each study has different criteria, making comparison somewhat nonsensical; however, our study identified a 63% incidence (29 out of 46) of SGLT2i-related KA or MA, which aligns with previous studies and shows no significant statistical difference, as evidenced by p-values of 0.598 and 0.278, respectively.
Patients undergoing cardiac surgery represent a unique demographic at an intersection of heightened risk for postoperative MA or KA associated with SGLT2i, primarily because they have pre-existing CV disease, which often necessitates the prescription of SGLT2i.Moreover, these patients typically undergo fasting and experience the surgical stress.Despite these compounded risk factors, the risk-to-benefit ratio overwhelmingly supports the continued use of SGLT2i for managing CV disease or T2D, and current guidelines uphold this stance.
With the rising use of SGLT2i for treating CV disease, we observed six patients who developed postoperative KA associated with these medications.Table 4 details these patients with confirmed ketone bodies who suffered from SGLT2i-related postoperative KA.Notably, there was no consistent pattern regarding the hours of onset of ketoacidosis among these patients.For our first patient (case #1) was involved in extended diagnostic process such as bedside transthoracic echocardiography and cardiac angiography and resulting in a 24-h diagnostic delay.This initial experience facilitated more straightforward diagnoses in subsequent cases, highlighting the importance of considering SGLT2i related EDKA in the care of post-cardiac surgery patients to prevent diagnostic delays.Interestingly, one patient (case #6) without a prior medical history of T2D also exhibited postoperative KA.This implies that these incidents may not be limited only to patients with diabetes, but might also include those using SGLT2i.Therefore, we referred to this condition not as SGLT2i related EDKA, but as postoperative MA or KA related to SGLT2i, omitting the term ' diabetic' .A mechanism associated with SGLT2 inhibition appears to induce an early transition to fat metabolism, leading to an accumulation of ketones and resulting in KA or MA 27 .
We conducted a retrospective review to assess the incidence and risk factors of postoperative MA or KA related to SGLT2i in 46 cardiac surgery patients; 63% (29 patients) developed postoperative MA associated with SGLT2i [Fig.1].Although the threshold for MA might differ across clinical laboratories, we characterized SGLT2i-related postoperative MA based on the criteria of a pH < 7.35 and an HCO3-≤ 22 mEq/L 28 .While our chosen threshold could be relatively liberal, we believe it is crucial to initially rule out benign but potentially concerning laboratory anomalies in post-cardiac surgery patients.
Cessation duration, according to the prescribing information 29,30 , dictates that SGLT2i should be discontinued 72 h prior to surgery..In the univariate analysis, a cessation duration of more than 72 h in the preoperative period did not result in a significant decrease in the occurrence of SGLT2i-related postoperative MA or KA (unadjusted OR, 0.58; 95% CI 0.16-2.20;p = 0.42) [Table 2].This lack of significance might suggest that the advised cessation period is shorter than actually needed.
A significant proportion of the cohort, 12 out of 46 (26%), were prescribed SGLT2i at the time of their CV diagnosis, within 1 month before their cardiac surgery.The univariate analysis indicated that a prescription duration exceeding 7 days significantly increased the incidence of SGLT2i-related postoperative MA (unadjusted OR, 11.7; 95% CI 1.65-237; p = 0.032*).This significance persisted in the multivariable analysis (adjusted OR, 31.58;95% CI 1.97-505.23;p = 0.014*) [Table 2].Our assumption is that the shift to fat metabolism induced by SGLT2 inhibition takes at least a few days, and patients who were prescribed for less than 7 days actually took SGLT2i for 3-5 days, considering the preoperative cessation period.
Furthermore, a subgroup analysis was performed to assess the impact of CPB running time on the occurrence of SGLT2i-related postoperative MA or KA.[Table 3] While ultrafiltration is employed to concentrate blood during CPB operations, reductions in both plasma colloid osmotic pressure and total protein concentration were noted following CPB use 19 .Following a decrease in protein levels, including drug-binding proteins,  2].For our strategy in managing post-cardiac surgery patients without kidney disease, we utilized a GIK solution to treat KA associated with SGLT2i.Electrolyte imbalances in post-cardiac surgery patients can provoke arrhythmias, making the restoration of potassium levels especially crucial in this patient population.
Based on our findings, we advocate for the verification of ketone bodies using urine or serum ketone tests in post-cardiac surgery patients who present with high anion-gap MA, a condition solely attributable to the preoperative use of SGLT2i.As a time and cost-effective approach, we assess urine ketone levels through routine urinalysis, which provides results within 30 min in these patients.When patients present with a urine ketone level exceeding 2 +, we subsequently conduct a serum ketone test, which often requires 2-3 days for results, and initiate GIK solution administration concomitantly.

Limitations
Given the nature of a retrospective observational study, ketone body tests were not routinely included in postoperative laboratory tests, so ketone body confirmations could not be conducted for all patients.Regarding ICU management, there was a lack of uniformity among physicians, and unnecessary injections of sodium bicarbonate affected anion gap and pH levels.Furthermore, this issue spoiled anion gap, which is crucial for differentiating postoperative hyperchloremic metabolic acidosis, thereby preventing the establishment of an accurate exclusion criteria.As a single-center study, there were deviations in operation entities, with a scarcity of aortic surgeries.

Conclusion
The CV benefits of SGLT2i in patients with CV disease are undeniably profound.Not every case of KA is necessarily harmful, but the FDA-issued warnings about these risks have not been sufficiently integrated into perioperative care protocols.The lack of awareness complicates diagnosis and treatment of postoperative metabolic issues related to SGLT2i.However, our research shows that timely diagnosis and proper treatment can ease the patient's transition from ICU support to general wards.
In describing the postoperative metabolic issues observed in our study, we chose not to use the term ' diabetes' to highlight the possibility that these conditions might extend beyond patients with T2D.Further research is needed concerning the optimal duration for preoperative cessation of SGLT2i.Additionally, it is imperative to study the effects of CPB institution on SGLT2i-related postoperative KA in patients, including the assessment of SGLT2i-induced KA among nondiabetic individuals.

Figure 1 .
Figure 1.Patient selection, exclusion criteria and risk factor analysis.From November 2019 to October 2022, we conducted a retrospective analysis on 823 cardiac surgery patients at our center, 46 of whom were preoperatively treated with SGLT2i, specifically dapagliflozin or empagliflozin.Based on postoperative arterial blood gas analysis, patients were categorized into two groups: those with postoperative metabolic acidosis and those without.SGLT2i sodium-glucose transporter 2 inhibitors, BMI body mass index, T2D type 2 diabetes, HbA1c Hemoglobin A1C, eGFR estimated glomerular filtration rate, CPB cardiopulmonary bypass.

Table 1 .
Basic characteristics of SGLT2i-related postoperative metabolic acidosis.This table outlines the characteristics of 46 postoperative metabolic acidosis related to SGLT2i.The average age was 62.2 ± 11.14 years, and BMI was 24.78 ± 3.3 kg/m 2 .Most patients were men (71.3%) with a history of T2D (91.3%).T2D type 2 diabetes, HbA1c Hemoglobin A1C, OHA oral hypoglycemia agents, eGFR estimated glomerular filtration rate, CABG coronary artery bypass grafting, LVAD left ventricular assist device, MV mechanical ventilator, ICU Intensive care unit.

Table 3 .
Subgroup Analysis: Impact of CPB Running Time on SGLT2i-Related Postoperative Metabolic Acidosis in patients with sufficient Prescription Duration.A subgroup analysis was conducted to assess the impact of CPB duration in patients with a sufficient SGLT2i prescription duration over 7 days (N = 40).The table shows that a CPB duration ≤ 60 min is associated with a significantly higher risk of SGLT2i-related postoperative metabolic acidosis(HR 2.94; 95% CI 0.50-5.38,p = 0.018*).SGLT2i sodium-glucose transporter 2 inhibitors, CPB cardiopulmonary bypass, HR hazard ratio, CI confidence interval.